Observations on Rituximab’s Early Success

By Gordon Broderick, Ph.D. Associate Professor, University of Alberta

Dr. Gordon Broderick

The news coming out of Norway this week regarding phase II clinical trials for treatment of CFS symptoms with rituximab [1] (marketed as Rituxan) is certainly encouraging. I would add that the apparent success of this approach might not be all that surprising.

Rituximab-action-NRR1-235×300Figure from Nature Reviews Rheumatology, Taylor and Lindorfer. Rituximab-opsonized B cells are subject to attack and killing by at least three pathways.

As mentioned by the authors, Rituximab is a B-cell suppressor used in the treatment of non-Hodgkin’s lymphoma. Abnormal B cell activity has long been suspected as playing a key role in CFS. As early as 2006, Maes and colleagues [2], in one of several related works, presented evidence of increased IgM antibodies directed specifically at cellular products of oxidative and nitrosative stress. The same year, our work with Dr. Suzanne Vernon and her colleagues also produced evidence of sustained oxidative stress in circulating immune cells based on their gene expression [3]. The immune system is also the body’s maintenance and clean-up crew, so it is not outlandish to think that a corresponding immune response would be mounted to recycle these cellular products. Coincidentally, Epstein-Barr virus (EBV) among other viral pathogens is a known promoter of oxidative stress [4] and this pathogen alters B cell status through this and other means. Once subjugated, B-lymphocytes also serve as a reservoir for sustained latent infection in EBV. Consistent with this, evidence of altered status in the B-lymphocytes of CFS patients was found in a study of gene expression conducted by our group [5] in collaboration with the Solve ME/CFS Initiative with Dr. Vernon as a co-author. Further work supported by the Association and the National Institutes of Health conducted with Drs. Nancy Klimas and Mary Ann Fletcher of the University of Miami documented immune signaling patterns suggestive of an over-active Th2 or B-cell mediated immune response in a cohort of 50 female CFS patients [6]. Both of these studies were cited in the report published by the Norwegian team. In a nutshell, these positive clinical trial results are not only welcome but they represent a logical continuation of a line of investigation that has been ongoing. Although significant symptom relief was obtained in a majority of patients (2 out of 3), it is important to note that not all patients were responsive to treatment. This once again highlights the heterogeneous nature of this patient population and the need for better sub-typing. Nonetheless, these remain very encouraging results and they support the next step of investigation, namely that of validation in a set of larger clinical trials. References: [1] Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, et al. (2011) Benefit from B-lymphocyte depletion using the anti-CD20 antibody Rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS ONE 6(10): e26358. doi:10.1371/journal.pone.0026358 [2] Maes M, Mihaylova I, Leunis JC. Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. Neuro Endocrinol Lett. 2006 Oct;27(5):615-21. [3] Broderick G, Craddock RC, Whistler T, Taylor R, Klimas N, Unger ER. Identifying illness parameters in fatiguing syndromes using classical projection methods. Pharmacogenomics. 2006 Apr;7(3):407-19. [4] Gruhne B, Sompallae R, Marescotti D, Kamranvar SA, Gastaldello S, Masucci MG The Epstein-Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species. Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2313-8. [5] Aspler AL, Bolshin C, Vernon SD, Broderick G. Evidence of inflammatory immune signaling in chronic fatigue syndrome: A pilot study of gene expression in peripheral blood. Behav Brain Funct. 2008 Sep 26;4:44. [6] Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun. 2010 Oct;24(7):1209-17. [Figure shown above, right] Taylor RP and Lindorfer MA. Drug Insight: the mechanism of action of rituximab in autoimmune disease—the immune complex decoy hypothesis. Nature Reviews Rheumatology 3, 86-95 (February 2007) | doi:10.1038/ncprheum0424 Dr. Gordon Broderick is an associate professor of pulmonary medicine in the department of medicine and a member of the faculty of medicine and dentistry at the University of Alberta. He serves as a member of the Solve ME/CFS Initiative’s Scientific Advisory Board.